Schizophrenia is a severe and chronic mental illness, with prevalence estimates ranging from 1.4 to 4.6 per 1000 population.
Schizophrenic disorders and depression are caused by a combination of genetic and environmental factors, which include, for schizophrenia, probable neurodevelopmental abnormalities in gray and white matter structures. Underlying the symptomatic phenomena in both diseases, disturbances in monoaminergic neurotransmission (e.g. serotonin, adrenaline, and noradrenaline) have been proposed.
These pathways are widely present in the CNS and, thus, are potentially capable of influencing many areas involved in emotional processing, cognition, and behavior. Until recently, the excess dopamine hypothesis was the major pathophysiological theory of schizophrenia, based largely on the effectiveness of D2 antagonists in controlling the acute exacerbations of this disease.
Symptoms of schizophrenia, which typically emerge during adolescence or early adulthood, are usually classified as positive, negative or cognitive. Positive symptoms include hallucinations, delusions and severe thought disorganization. Negative symptoms are a group of deficits comprising flat affect, apathy, poverty of speech, anhedonia and social withdrawal. Cognitive symptoms, such as deficits in attention and working memory, are prominent features of the illness and have been identified as powerful predictors of social outcome.
Current atypical antipsychotics are efficacious primarily in the management of positive symptoms, yet have minimal effects on negative symptoms and cognitive function, besides being associated with significant side-effects. Efficacy on cognitive symptoms and improvement of negative symptoms are the highest unmet need in schizophrenia.
First generation drugs are effective but associated with significant incidence of extrapyramidal symptoms, whereas second-generation (atypical) antipsychotics appear to have less incidence of extrapyramidal side-effects and may be more effective in treating cognition but increase the incidence and severity of metabolic syndrome.
A common antipsychotic drug for the treatment of schizophrenia is olanzapine. Olanzapine (Zyprexa) belongs to a drug class known as atypical antipsychotics. Other members of this class include clozapine (Clozaril), risperidone (Risperdal), aripiprazole (Abilify) and ziprasidone (Geodon). Olanzapine binds to alpha-1, dopamine, histamine, muscarinic and serotonin type 2 (5-HT2) receptors.
Olanzapine is approved for the treatment of psychotic disorders, long term treatment of bipolar disorders and in combination with fluoxetine for the treatment of depressive episodes associated with bipolar disorders and for the treatment of resistant depression.
The treatment with antipsychotic drugs, such as olanzapine, may lead to serious side effects. The Food and Drug Administration requires all atypical antipsychotics to include a warning about the risk of developing hyperglycemia and diabetes, both of which are factors in the metabolic syndrome. These effects may be related to the drug's ability to induce weight gain. Cardiometabolic adverse effects, such as weight gain, obesity, hypertension and lipid and glucose abnormalities, are particularly problematic during development because they predict adult obesity, the metabolic syndrome, cardiovascular morbidity and malignancy, especially if used in children and adolescents.
There may be an increased risk of increased blood sugar levels and diabetes with olanzapine as well as the other antipsychotic medications in its class.
Many paediatric and adolescent patients who received second-generation antipsychotic medications experienced significant weight gain, along with varied adverse effects on cholesterol and triglyceride levels and other metabolic measures, according to a study in the October 28 issue of JAMA (JAMA, 2009 Oct. 28, 302 (16), 1765-73).
“Increasingly, the cardiometabolic effects of second-generation antipsychotic medications have raised concern. Cardiometabolic adverse effects, such as age-inappropriate weight gain, obesity, hypertension, and lipid and glucose abnormalities, are particularly problematic during development because they predict adult obesity, the metabolic syndrome, cardiovascular morbidity, and malignancy,” the authors wrote. The cardiometabolic effects of these medications have not been sufficiently studied in children and adolescent patients who have not previously received them, according to background information in the article.
Christoph U. Correll, MD, Zucker Hillside Hospital, North Shore-Long Island Jewish Health System, Glen Oaks, and The Feinstein Institute for Medical Research, Manhasset, N.Y., and colleagues conducted a study of weight and metabolic changes in a group of 272 paediatric patients (ages 4 to 19 years) who had not previously received antipsychotic medication. Patients had mood spectrum (47.8%), schizophrenia spectrum (30.1%), and disruptive or aggressive behaviour spectrum (22.1%) disorders. Fifteen patients who refused participation or were nonadherent to medications served as a comparison group. Patients were treated with the antipsychotic medications aripiprazole, olanzapine, quetiapine, or risperidone for 12 weeks.
After a median of 10.8 weeks of treatment, weight increased by an average of 8.5 kg (18.7 lbs) with olanzapine (n=45), by 6.1 kg (13.4 lbs) with quetiapine (n=36), by 5.3 kg (11.7 lbs) with risperidone (n=135), and by 4.4 kg (9.7 lbs) with aripiprazole (n=41) compared with minimal weight change of 0.2 kg (0.4 lbs) in the untreated comparison group (n=15). “Each antipsychotic medication was associated with significantly increased fat mass and waist circumference,” the authors wrote. “Altogether, 10% to 36% of patients transitioned to overweight or obese status within 11 weeks.”
The researchers also found that adverse changes during the study period reached statistical significance for olanzapine and quetiapine for total cholesterol, triglycerides, non-high-density lipoprotein (HDL) cholesterol, and ratio of triglycerides to HDL cholesterol. “With risperidone, levels of triglycerides increased significantly. Metabolic baseline-to-endpoint changes were not significant with aripiprazole or in the untreated comparison group. Patients receiving quetiapine had modestly higher incidence rates of hyperglycaemia and the metabolic syndrome and patients receiving olanzapine experienced the highest incidence rates.”
The authors noted that these results are concerning because they include fat mass and waist circumference, which are associated with the metabolic syndrome in adults treated with antipsychotic medications and heart disease in the general population. “Moreover, abnormal childhood weight and metabolic status adversely affect adult cardiovascular outcomes via continuation of these risk factors or independent or accelerated mechanisms.”
“Our results, together with data from first-episode studies, suggest that guidelines for antipsychotic medication exposure for vulnerable paediatric and adolescent patients naïve to antipsychotic medication should consider more frequent [eg, biannual] cardiometabolic monitoring after the first 3 months of treatment. Finally, in view of poor physical health outcomes and suboptimal metabolic monitoring in the severely mentally ill, the benefits of second-generation antipsychotic medications must be balanced against their cardiometabolic risks through a careful assessment of the indications for their use, consideration of lower-risk alternatives, and proactive adverse effect monitoring and management,” the authors concluded.
In an accompanying editorial, Christopher K. Varley, MD, and Jon McClellan, MD, of Seattle Children's Hospital, Seattle, Wash., wrote that these findings indicate there are other factors to consider regarding the use of atypical antipsychotic medications in children and adolescents.
“These medications can be lifesaving for youth with serious psychiatric illnesses such as schizophrenia, classically defined bipolar disorder, or severe aggression associated with autism. However, given the risk for weight gain and long-term risk for cardiovascular and metabolic problems, the widespread and increasing use of atypical antipsychotic medications in children and adolescents should be reconsidered.”
There is a need for new therapies with improved safety and tolerability profile over current atypical antipsychotics. For example, new treatments should not be associated with such side effects or adverse reactions as described above.
Metabolic syndrome is a combination of medical disorders that increase the risk of developing diabetes and cardiovascular disease. Risk factors include for example abdominal obesity (excessive fat tissue in and around the abdomen), blood fat disorders, elevated blood pressure, insulin resistance or glucose intolerance.
Trace amines (p-tyramine, β-phenylethylamine (PEA), octopamine, and tryptamine) are present throughout the CNS, closely paralleling the monoaminergic pathways, and at endogenous levels much lower than these neurotransmitters. Their scarcity is due, in part, to their high turnover rate being good substrates for MAO A/B. Trace amines are structurally related to, co-localized, and released with classical biogenic amine neurotransmitters. They are suggested to be neuromodulators of classical neurotransmitters like dopamine, serotonin and noradrenaline whose levels are the target of all known antidepressants and most antipsychotics currently on the market or in clinics. Abnormalities in trace amine physiology have long been associated with schizophrenia and mood disorders. In schizophrenia, increased urinary levels of PEA (the so-called endogenous amphetamine), and alterations in the metabolism of tryptamine and p-tyramine have been proposed, including enzymes involved in the synthetic and catabolic pathways of these molecules.
Therefore, the identification of specific receptors for trace amines could lead to the development of specific drugs targeting this novel neuromodulator system with clinical applications in disorders such as schizophrenia, bipolar disorder and depression.
Recently, a family of G-protein coupled receptors has been identified and named Trace Amine-Associated Receptors (TAAR), TAAR1 being the best characterized of these receptors, and the main target for endogenous trace amines. TAAR1 is expressed in brain structures associated with psychiatric disorders, in particular in key areas where modulation of dopamine (ventral tegmental area) and serotonin (dorsal raphe) occurs but also in the amygdala, hypothalamus, nucleus accumbens, rhinal cortices, and subiculum. TAAR1 may be a novel target for antipsychotic drugs with high potential for differentiation, exploring a fundamentally new mechanism of action based on the modulation of dopaminergic and glutamatergic neurotransmission. Therefore, even in the absence of trace amine deficiencies, neuromodulatory effects on the monoaminergic pathways could predictably lead to an improvement in schizophrenia. Also, the TAAR genes map closely to one of the major genetic susceptibility locus for schizophrenia, SCZD5.